Vasopressin, a neurohypophyseal neuropeptide produced in the hypothalamus, is involved in water metabolism homeostasis, renal function, mediation of cardiovascular function, non-opioid mediation of tolerance for pain, and regulation of temperature in mammals. In addition to being released into the circulation via the posterior pituitary, vasopressin acts as a neurotransmitter in the brain. Three vasopressin receptor subtypes, designated V1a, V1b, and V2 have been identified. The human V1a receptor has been cloned (Thibonnier et al., The Journal of Biological Chemistry, 269(5), 3304–3310 (1994)), and has been shown by radioligand binding techniques to be present in vascular smooth muscle cells, hepatocytes, blood platelets, lymphocytes and monocytes, type II pneumocytes, adrenal cortex, brain, reproductive organs, retinal epithelium, renal mesangial cells, and the A10, A7r5, 3T3 and WRK-1 cell lines (Thibonnier, Neuroendocrinology of the Concepts in Neurosurgery Series 5, (Selman, W., ed), 19–30, Williams and Wilkins, Baltimore, (1993)).
Structural modification of vasopressin has provided a number of vasopressin agonists (Sawyer, Pharmacol. Reviews, 13, 255 (1961)). In addition, several potent and selective vasopressin peptide antagonists have been designed (Lazslo et al., Pharmacological Reviews, 43, 73–108 (1991); Mah and Hofbauer, Drugs of the Future, 12, 1055–1070 (1987); Manning and Sawyer, Trends in Neuroscience, 7, 8–9 (1984)). Their lack of oral bioavailability and short half-life, however, have limited the therapeutic potential of these analogs. While novel structural classes of non-peptidyl vasopressin V1a antagonists have been discovered (Yamamura et al., Science, 275, 572–574 (1991); Serradiel-Le Gal et al., Journal of Clinical Investigation, 92, 224–231 (1993); Serradiel-Le Gal et al., Biochemical Pharmacology, 47(4), 633–641 (1994)), a clinical candidate has yet to be identified.
The general structural class of substituted 2-(azetidin-2-on-1-yl)acetic acid esters and amides are known as synthetic intermediates for the preparation of β-lactam antibiotics (see e.g. U.S. Pat. No. 4,751,299).